AB0133 TARGETING INFLAMMATION RESOLUTION IN SYSTEMIC SCLEROSIS: PRECLINICAL DATA OF A NEW DISEASE MODIFYING BIOLOGIC DRUG CANDIDATE RESOLVIX
Authors: F. Bonnefoy, S. Perruche
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic sclerosis (SSc) is a complex immune-mediated connective tissue disorder characterized by microvascular damage, inflammatory cell infiltration, and excessive deposition of extracellular matrix proteins (ECMs) resulting in fibrosis in the skin and various internal organs. Limited treatment options are currently available in the clinic and are mostly focusing on symptom control with limited impact on disease progression. New treatment approaches are needed to address the complex dysregulated pathways and disease drivers to develop effective therapies. While the pathophysiology of SSc remains incompletely understood it is well-recognized that progressive chronic inflammation is a part of the disease and its progression. Accumulation of apoptotic cells in tissues and defective clearance of these cells contributing to unresolved tissue repair is emerging as a root cause leading to sustained uncontrolled chronic inflammation and fibrosis. Naturally ending and resolving chronic inflammation to initiate healing and repair processes could present a novel therapeutic approach for SSc. Resolvix, a next generation biological drug candidate under development, harnesses a complex mix of naturally occurring pro-resolutive factors emitted by human cells, has demonstrated promising disease modifying effects in models of experimental arthritis and inflammatory bowel disease. Objectives The objective of our preclinical study presented here, was to evaluate the potential therapeutic effects of Resolvix in experimental models of SSc. Methods Two established inducible preclinical models of SSc (bleomycin (BLM) and HOCl) were used to monitor the impact of Resolvix mouse equivalent versus a control treatment on skin (thickness and collagen deposition), lung (leucocyte infiltration and alveolar macrophage efferocytosis) and lymphoid organs/blood (Tregs) as well as selected plasma proteins. A single treatment or respective controls were administrated intra-venously at 3 weeks post disease induction and mice were monitored daily and sacrificed for analysis after 3 weeks post treatment. Results In our hands both preclinical models clearly show phenotypes associated with sclerosing processes of SSc. In both models we could show a significant reduction of skin thickening and collagen deposition in skin samples after a single treatment with Resolvix when compared to controls. Leucocyte infiltrates particularly evident in the HOCl model were significantly reduced by the Resolvix treatment in skin and lung tissues. Interestingly, alveolar macrophages collected from broncho-alveolar lavage (BAL) fluids of the diseased mice in both model systems demonstrated a significant reduction of efferocytosis capacity (eliminating apoptotic cells) a sign of uncontrolled ongoing chronic inflammation and recently reported in SSc patients 1 . Resolvix treatment successfully restored the efferocytosis activity to comparable levels detected in healthy mice. In addition, Foxp3 + regulatory T cells were increased in the blood of BLM-mice treated with Resolvix. Plasma concentrations of IL-6 and TNF-α were not modified between controls, treated and non-treated mice. Conclusion Collectively our preliminary data demonstrate that harnessed pro-resolutive factors making up Resolvix are able to revert skin fibrosing processes, control inflammatory cell infiltration and restore defective macrophage efferocytosis as a novel a therapeutic approach in SSc. Resolvix should be considered as a next generation disease modifying biological drug candidate for further development for the treatment of SSc. References [1]Ballerie et al., 2019, Immunology &amp; Cell Biology Efferocytosis capacities of blood monocyte-derived macrophages in systemic sclerosis. Disclosure of Interests None declared